The objective of this research is to identify factors that create risk for the birth of a child with a neural tube defect (NTD). These defects, which include the fatal brain malformation, anencephaly, and the handicapping condition, spina bifida or meningomyelocele, spina bifida or meningomyelocele, occur in 1 to 2 of 1,000 births. Like other common birth defects, NTD are caused by a complex interaction of genetic and environmental factors, with precise etiologies poorly understood. The 160 probands to be enrolled in the study (half for Boston and half from Ottawa) will be categorized according to the level of the lesion and the presence or absence of non-neural malformations, as these phenotype features may be related to different genetic etiologies. Detailed medical, pregnancy and family history data will be obtained by structured interview. Cases with known malformation syndromes or identifiable risk factors such as maternal insulin-dependent diabetes mellitus or in utero valproic acid exposure will be excluded. Mothers, fathers, and normal and damaged offspring will be typed for genes hypothesized to be related to NTD, viz., HLA, TF, GM, and KM, as well as for control genes. These subject families will be compared with 800 families without NTD to determine whether familial constellations of specific genes -- parental or maternal and fetal -- may combine to produce high risk for NTD or particular types of NTD. We will test the prior hypothesis, developed from preliminary data (NEJM 313:925,1985), that there is an association between the presence of maternal transferrin C3 or B allele and HLA allele sharing in a significant number of couples who have had a child with NTD. If confirmed, this would indicate an interactive effect of genes on chromosomes 3 (transferrin) and 6 (HLA) in the occurrence of NTD. Further, we will explore the suggestion from unpublished data that couples with GM and KM phenotype identity have increased risk for producing an anencephalic fetus. This study differs form previous studies of the genetic causes of NTD by including a family-based analysis of the transmission to affected and unaffected offspring in NTD families of "high risk" genes compared with control genes -- and as compared with the transmission patterns of these same genes in families without NTD. The study has the potential to identify specific factors that may contribute to common, multifactorial, developmental defects.